clinical topic updates

Toward Personalized Insomnia Therapy

by Ravi Allada, MD

Overview

Although true precision therapy remains on the horizon, physicians have many ways to tailor available insomnia treatments to each patient. Our featured expert discusses recent developments in the pursuit of personalized insomnia treatment.

Expert Commentary

Ravi Allada, MD

Edward C. Stuntz Distinguished Professor of Neuroscience
Chair, Department of Neurobiology
Northwestern University
Evanston, IL

“I think that this type of precision approach might be more broadly applicable once we start to define the underlying physiological disruption, at the level of gene expression.” 

Ravi Allada, MD

While many effective pharmacologic and behavioral treatments for insomnia are available and can be individualized in numerous ways, true precision therapy for sleep disturbances remains largely in the realm of research. This is true, in part, because there are many primary and secondary causes of insomnia, with many comorbidities that may impact sleep. The deep mechanistic, molecular, and physiologic understanding of each type of insomnia that would guide diagnosis and personalized treatment does not yet exist to the degree that it does for other conditions. Nonetheless, progress is being made in understanding the molecular aspects of insomnia, particularly in insomnias that stem from disruption of the circadian clock. These are not the most common types of insomnia, but we now recognize, to the molecular genetic level, many of the mechanisms that lead to changes in the timing of circadian control of sleep.

Today’s treatments range from cognitive behavioral therapy to pharmacotherapies that act on differing neurotransmitter systems. Available medications have distinct side-effect profiles, with differing half-lives, and treatment can be geared toward problems with sleep onset, sleep maintenance, or both. The gamma-aminobutyric acid (GABA) system is the major inhibitory neurotransmitter in the central nervous system (CNS), and the side-effect profiles of GABA-based drugs are fairly broad, including tolerance, withdrawal symptoms, and dependence. Orexin receptor antagonists are relatively recent additions to the landscape, with phase 3 clinical trials reporting favorable efficacy and safety profiles for both suvorexant and lemborexant. While having broad importance to brain function, the orexin system involves a relatively small number of neurons that produce the orexin neuropeptide. With orexin inhibitors, you are going from a set of compounds that impact a large fraction of the CNS (ie, the GABA system) to a set of compounds that have a more discrete effect on the CNS. That in and of itself has theoretical advantages. Further, given that most therapeutics for insomnia have been in the GABA-based class for quite a long time, having an additional option that is effective and safe gives clinicians another tool in their toolkit to address insomnia.

However, to achieve the goal of more personalized treatment of insomnia, a better understanding of the differing phenotypes and molecular bases for commonly encountered forms of insomnia is needed. One of the more promising steps toward this goal is the recent work aimed at developing a simple blood test that could be administered in the doctor’s office to assess physiological time using transcriptional biomarkers. Theoretically, such testing might improve the diagnosis of circadian disorders and optimize the delivery of treatments. I think that this type of precision approach might be more broadly applicable once we start to define the underlying physiological disruption, at the level of gene expression. Other research is being conducted in areas such as metabolomics and proteomics; these approaches are expected to bear fruit in terms of further characterizing the very complex and multifactorial causes of insomnia. They may be the key to solving this puzzle pipeline from diagnosis to therapeutics.

References

Allada R, Cirelli C, Sehgal A. Molecular mechanisms of sleep homeostasis in flies and mammals. Cold Spring Harb Perspect Biol. 2017;9(8):a027730. doi:10.1101/cshperspect.a027730

Braun R, Kath WL, Iwanaszko M, et al. Universal method for robust detection of circadian state from gene expression. Proc Natl Acad Sci U S A. 2018;115(39):E9247-E9256. doi:10.1073/pnas.1800314115

Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016;79(2):136-148. doi:10.1016/j.biopsych.2014.10.003

Hughes ME, Abruzzi KC, Allada R, et al. Guidelines for genome-scale analysis of biological rhythms. J Biol Rhythms. 2017;32(5):380-393. doi:10.1177/0748730417728663

Krystal AD, Prather AA, Ashbrook LH. The assessment and management of insomnia: an update. World Psychiatry. 2019;18(3):337-352. doi:10.1002/wps.20674

Laing EE, Möller-Levet CS, Dijk D-J, Archer SN. Identifying and validating blood mRNA biomarkers for acute and chronic insufficient sleep in humans: a machine learning approach. Sleep. 2019;42(1):zsy186. doi:10.1093/sleep/zsy186

Rosenberg R, Murphy P, Zammit G, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254

Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349. doi:10.5664/jcsm.6470

Sengupta A, Weljie AM. Metabolism of sleep and aging: bridging the gap using metabolomics. Nutr Healthy Aging. 2019;5(3):167-184. doi:10.3233/NHA-180043

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